(−)-Verbenone derivatives

Abstract

A description is given here of novel solid and stable derivatives of (−)-verbenone having formula (I) wherein, when X=O Z=H, ═CHAr, ═C(OH)COOEt, ═NOR; Y=H, NH 2 , NH 3 +X 1 −, NHCOAr, NHCOR, NHCONHR, NHCONHAr, X 1 -=pharmaceutically acceptable anion; Ar-aryl or heteroaryl, preferably phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-acetoxyphenyl; R=H, C 1 -C 4 alkyl, C 4 -C 6 cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COCH 2 COOEt, CH 2 C 6 H 5 ; and, when X=dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino: Y=H; Z=H, CONHAr, COHNR; Ar=aryl, preferably phenyl; R=H, C 1 -C 4 alkyl, C 4 -C 6 cycloakyl. A description is also given of the processes for the preparation of these derivatives and of the novel intermediates used in those processes. The novel derivatives are characterized by their solubility in water; some of them also have a high anti-inflammatory activity.

What is claimed is:  
     
       1. A compound having the formula                    
       wherein, when X=O 
       Z=H, ═CHAr, ═C(OH)COOEt, ═NOR;  
       Y=H, NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR, NHCONHAr;  
       X 1   − =pharmaceutically acceptable anion;  
       Ar=aryl selected from among the group consisting of: phenyl, 4chlorophenyl, 2-furyl, 2-thienyl, 2 hydroxyphenyl and 2-acetophenyl;  
       R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COOCH 2 COOEt, CH 2 C 6 H 5 ;  
       with the proviso that when X=O ad Y=HZ is other than H;  
       and when X=dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino;  
       Y=H; Z=EL CONHAr, CONHR; Ar=aryl; R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl; with the proviso that when Z=H, X is other than pyrrolidino.  
     
     
       2. A compound according to  claim 1  having the formula                    
       wherein: 
       when Y=H Z=═CHAr, ═C(OH)COOEt, ═NOR; or, alternatively,  
       when Z=H, Y=NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR, and wherein:  
       X 1   − =5-sulphosalicylate, tartrate, 10-camphosulphonate;  
       Ar=phenyl 4-chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-acetoxyphenyl;  
       R=H, C 1 -C 4  alkyl C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COCH 2 COOEt, CH 2 C 6 H 5 .  
     
     
       3. A compound according to  claim 1  having the formula                    
       wherein: 
       X=dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino;  
       Z=H, CONHAr, —CONHR;  
       Ar=phenyl;  
       R=H, methyl cyclohexyl;  
       with the proviso that when when Z=H, X is other than pyrrolidino.  
     
     
       4. A compound having the formula                    
       wherein X 1   − is a pharmaceutically acceptable anion. 
     
     
       5. A compound according to  claim 4  wherein the pharmaceutically acceptable anion is selected from 5-sulphosalicylate, tartrate, 10-camphosulphonate. 
     
     
       6. 3-amino-(−)-verbenone-5-sulphosalicylate. 
     
     
       7. A pharmaceutical composition containing at least one compound according to claims  1 - 6  as active ingredient together with the normal excipients and/or co-adjuvants. 
     
     
       8. A compound having the formula                    
     
     
       9. A compound having the formula                    
     
     
       10. A compound having the formula                    
       wherein X=dimethylamino, diethylamino, pyrrolidino, piperidino and morpholino. 
     
     
       11. A process for the preparation of a compound according to  claim 4  comprising the following steps: 
       a) nitrosation of the methyl in the 4 position of (−)-verbenone to give 10-hydroxyiminoverbenone;  
       b) reduction of 10-hydroxyiminoverbenone to give 3-aminoverbenone;  
       c) treatment of 3-aminoverbenone with a pharmacologically acceptable organic acid.  
     
     
       12. A process according to  claim 11 , characterized in that the pharmacologically acceptable organic acid is selected from 5-sulphosalicylic acid, L-(+)-tartaric acid and (1S)-(+)-10-camphosulphonic acid. 
     
     
       13. A process according to  claim 11 , characterized in that the nitrosation of the methyl in the 4 position of (−)-verbenone is carried out by means of isoamyl nitrite in the presence of metallic sodium. 
     
     
       14. A process according to  claim 11 , characterized in that the reduction of the 10-hydroxyiminoverbenone is carried out by means of zinc in the presence of sodium hydroxide. 
     
     
       15. A method for preparing a pharmaceutical compound wherein the formula of a composition is:                    
       when X=O 
       Z=H, ═CHAr, ═C(OH)COOEt, ═NOR;  
       Y=H, NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR, NHCONHAr;  
       X 1   − =pharmaceutically acceptable anion;  
       Ar=aryl selected from among the group consisting of phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2 hydroxyphenyl and 2-acetophenyl;  
       R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COOCH 2 COOEt, CH 2 C 6 H 5 ;  
       with the proviso that when X=O and Y=H, Z is other than H;  
       and when X=dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino:  
       Y=H; Z=H, CONHAr, CONHR; Ar=aryl; R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl;  
       with the proviso that when Z=H, X is other than pyrrolidino,  
       and includes a step in which said composition is used in the preparation of said pharmaceutical compound.  
     
     
       16. The method as rectied in  claim 15 , wherein said pharmaceutical composition has anti-inflammatory activities. 
     
     
       17. The method as rectied in  claim 15 , wherein said pharmaceutical composition has anti-muco-regulatory activities. 
     
     
       18. A method for making a compound, said compound having the formula:                    
       when X=O 
       Z=H, ═CHAr, ═C(OH)COOEt, ═NOR;  
       Y=H, NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR, NHCONHAr;  
       X 1   − =pharmaceutically acceptable anion;  
       Ar=aryl, selected from among the group consisting of: phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2 hydroxyphenyl and 2-acetophenyl;  
       R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COOCH 2 COOEt, CH 2 C 6 H 5 ;  
       with the proviso that when X=O and Y=H, Z is other than H;  
       and when X=dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino;  
       Y=H; Z=H, CONHAr, CONHR; Ar=azyl; R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl;  
       with the proviso that when Z=H, X is other than pyrrolidino,  
       including a step wherein a composition having the formula selected from the group consisting of;                    
        is used as an intermediate in the preparation of said compound.  
     
     
       19. A method for making a compound, wherein said compound has the following formula:                    
       when X=O 
       Z=H, ═CHAr, ═C(OH)COOEt, ═NOR;  
       Y=H, NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR, NHCONHAr;  
       X 1   − =pharmaceutically acceptable anion;  
       Ar=aryl, selected from among the group consisting of phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2 hydroxyphenyl and 2-acetophenyl;  
       R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COOCH 2 COOEt, CH 2 C 6 H 5 ;  
       with the proviso that when X=O and Y=H, Z is other than H;  
       and when X=dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino;  
       Y=H; Z=H CONHAr, CONHR; Ar=aryl, R=H C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl; with the proviso that when Z=H, X is other than pyrrolidino,  
       including a step in which (−)-verbenone is used as an intermediate in the preparation of said compound.  
     
     
       20. The method of making a pharmaceutical compound as recited in  claim 15 , wherein the formula of said composition is:                    
       when Y=H Z=═CHAr, ═C(OH)COOEt, ═NOR; or, alternatively,  
       when Z=H, Y=NH 2 , NH 3   + X 1   − , NHCOAr, NHCOR, NHCONHR; and wherein:  
       X 1   − =5-sulphosalicylate, tartrate, 10-camphosulphonate;  
       Ar=phenyl, 4-chlorophenyl, 2-furyl, 2-thienyl, 2-hydroxyphenyl, 2-acetoxyphenyl;  
       R=H, C 1 -C 4  alkyl, C 4 -C 6  cycloalkyl, CH 2 COOH, CH 2 COOEt, CH 2 COCH 3 , CH 2 CN, CH 2 COCH 2 COOEt, CH 2 C 6 H 5.    
     
     
       21. The method of making a pharmaceutical compound as recited in  claim 15 , wherein the formula of said composition is:                    
       X=dimethylamino, diethylamino, pyrrolidino, piperidino or morpholino;  
       Z=H, CONHAr, —CONHR;  
       Ar=phenyl;  
       R=H, methyl, cyclohexyl;  
       with the proviso that when when Z=H, X is other than pyrrolidino.  
     
     
       22. A method of making a pharmaceutical compound, wherein the formula of a composition is                    
       wherein X 1   −  is a pharmaceutically acceptable anion and includes a step wherein said composition is used in the preparation of said pharmaceutical compound. 
     
     
       23. The method of making a pharmaceutical compound as recited in  claim 22  wherein the pharmaceutically acceptable anion is selected from the group consisting of: 5-sulphosalicylate, tartrate, and 10-camphosulphonate. 
     
     
       24. A method of making a pharmaceutical compound including the step of using 3-amino-(−)-verbenone-5-sulphosalicylate in the preparation of said pharmaceutical compound. 
     
     
       25. The compound recited in  claim 1 , wherein when X=dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino, Ar=phenyl.